DE3223833A1 - 1-CYAN-2-METHYL-3- <2 '- (((5' '- METHYLIMIDAZOL-4' '- YL) -METHYL) -THIO) -AETHYL> -GUANI DINMONOHYDRATE (CIMETIDINE MONOHYDRATE) AND METHOD FOR PRODUCING THE SAME FROM 1-CYAN-2-METHYL-3- <2 '- (((5' '- METHYLIMIDAZOL-4' '-YL) -METHYL) -THIO) -AETHYL> -GUANIDIN A (CIMETIDIN A) AND THE FIRST CONTAINING IT DRUG - Google Patents

Abstract

The invention relates to 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine monohydrate [cimetidine monohydrate] of the formula the subject matter of the invention is also a process for the preparation of this compound, in which a warm aqueous, optionally also methylamine-containing, homogeneous solution of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine [cimetidine] poured onto ice and the precipitated 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine monohydrate [cimetidine monohydrate] is separated. The invention also relates to a process for the preparation of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine A [ Cimetidine A], in which the 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine monohydrate [cimetidine monohydrate] from a optionally aqueous solvent is recrystallized. The invention also relates to medicaments containing 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine monohydrate [cimetidine monohydrate].

Description

cover sheet

The invention relates to the new monohydrate of the histamine H-2 receptors inhibiting 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} - äthyl> -guanidines [Cimetidines], the cimetidine monohydrate, as well as a process for the production of the same and of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] - thio} -äthyl> -guanidine A [cimetidine A] and the drug containing the former, especially those with an inhibitory effect on the histamine H-2 receptors.

Several crystal modifications of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidines [cimetidines] are known from the literature. According to German Offenlegungsschrift No. 2,742,531, the crystal modification A which is most suitable for pharmaceutical purposes is obtained by crystallization from an anhydrous medium. The crystal modifications B and C crystallize out from an aqueous medium. Similar findings are contained in another publication (Gazzetta Chim. Ital. 109 [1979], 535 to 539), the main conclusion of which is that the formation of the individual crystal modifications from aqueous media is accidental and not controllable.

Of the processes known for the preparation of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidines [cimetidines], im deserve In terms of practice, in particular the processes described in Belgian patent specification 804 144 Interest:

a) Reaction of N-cyano-N '- <2 - {[(5'-methylimidazol-4'-yl) -methyl] -thio} -ethyl> -S- <methyl> -isothiourea with methylamine in alcohol. b) Reaction of 4-methyl-5 - [(2'-aminoethyl) -thiomethyl] -imidazole with N-cyano-N ', S- (dimethyl) -isothiourea in acetonitrile by heating to the boil for a long time.

c) Reaction of N-methyl-N '- <2 - {[(5'-methylimidazol-4'-yl) -methyl] -thio} -ethyl> -thiourea with lead cyanamide in a mixture of dimethylformamide and acetonitrile.

According to the above known process b), the product is obtained in a yield of only 20% after the chromatographic purification (J. Med. Chem. 20 [1977], 901) and also the yield of the above known process c) [40%] does not meet the requirements placed on the last stage of a synthesis. The use of a lead-containing reagent in the last stage is also disadvantageous.

The above known process a) appears to be problem-free with regard to the yield, but it is by no means as regards the conduct of the reaction and the work-up of the reaction mixture. According to the Belgian patent [Example 1 (c), point (ii)], the reaction is carried out at room temperature with a large excess of methylamine in alcohol, then the reaction mixture is evaporated and the residue is crystallized from a mixture of isopropanol and petroleum ether. This process has the following disadvantages: When the reaction is carried out at room temperature, the methyl mercaptan is not expelled, and when the reaction mixture is evaporated, the evolution of gas is so rapid that adsorption of the gases is not possible. The 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine [cimetidine], i.e. the desired product, is as evaporation residue, which also contains all impurities and by-products. These by-products and

Impurities cannot be removed in the manner described in Belgian patent 804 144, and the quality of the crystallized product is unsatisfactory.

In the preparation of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidines [cimetidines] in an anhydrous medium recrystallization and a certain, albeit inadequate, purification of this compound by crystallization from anhydrous organic solvents, the pharmaceutically acceptable crystal modification A of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazole -4 "-yl) -methyl] -thio} -ethyl> -guanidines [Cimetidines] is obtained.

In on improving the production of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidines [Cimetidines] by reacting des N-cyano-N '- <2 - {[(5'-methylimidazol-4'-yl) -methyl] -thio} -ethyl> -S- <methyl> -isothiourea [(produced according to Belgian patent 804 144 or according to the Hungarian patent application with the file number 899/80)] or the monohydrate [produced by reacting 5- (methyl) -4- (hydroxymethyl) imidazole hydrochloride and cysteamine hydrochloride in equimolar amounts in the melt and reacting the cooled melt with Equimolar amounts of sodium carbonate and dimethyl dithiocarbonate (N-cyano) imide {Hungarian patent application with the file number 899/80}] or of hydrohalides of the same [can be produced like the monohydrate mentioned with the difference that only half the equimolar amount of sodium carbonate is used and in the case of the production of hydrohalides other than the hydrochloride of d en corresponding other hydrohalides of 5- (methyl) -4- (hydroxymethyl) -imidazole and cysteamine is assumed

{Hungarian patent application with the file number 899/80}] with methylamine-directed experiments it was found that when the reaction is carried out in an aqueous medium, a temperature range exists in which the evolution of methyl mercaptan proceeds uniformly. According to this process, which is the subject of the applicant's German patent application corresponding to the Hungarian patent application with the file number 1876/81 of June 26, 1981, the aforementioned reaction is carried out in an aqueous medium at temperatures from 30 ° C to the boiling point of the solution . As a result, the by-product methyl mercaptan can be chemically destroyed (by burning or oxidation with hypochlorite) more easily than if it were created suddenly or in bursts. This is due to the fact that the methylamine delays the escape of the methyl mercaptan at room temperature and also slightly above this due to loose salt formation. Furthermore, while the methylamine reagent also escapes in considerable quantities in an alcoholic medium when heated, it can be heated to 50 to 60 ° C. in an aqueous medium, thereby eliminating the methyl mercaptan. As a result, the methylamine can be used in a smaller excess, which simplifies the work and increases the economy; a 1 to 4 molar excess (2 to 5 molar equivalents of methylamine per molar equivalent of N-cyano-N '- <2 - {[(5'-methylimidazol-4'-yl) methyl] - thio} -äthyl> -S- <methyl> -isothiourea or monohydrate or hydrohalide of the same) sufficient, while in literature a more than 10 molar excess is recommended.

The advantages of the last-mentioned process carried out in an aqueous medium appear not only in the field of safety engineering and environmental protection and are also not limited to a reduction in the amount of methylamine required, but also come from one expresses greater purity of the end product. The reaction produces S, S'-bis [2- (N-cyano-N'-methyl) guanidinoethyl] disulfide as a by-product, the preparation of which is described in German Offenlegungsschrift No. 29 44 257 (in insufficient purity). For the S, S'-bis- [2- (N-cyano-N'-methyl) -guanidinoethyl] disulfide to appear as an impurity, it is not absolutely necessary that it be used as the starting material for the production of the starting materials of the last-mentioned process usable cysteamine hydrochloride is contaminated with disulfide. The S, S'-bis- [2- (N-cyano-N'-methyl) -guanidinoethyl] -disulfide can also be formed from cysteamine hydrochloride, dimethyl dithiocarbonate- (N-cyano) -imide [dimethyl cyanimidodithiocarbonate] and methylamine furthermore, as it was found, also by splitting the bond C - S in the side chain of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] - thio} -äthyl> -guanidines [cimetidines] arise. The exchange of different nucleophilic groups is a well known fact in Mannich compounds. It was found that the by-product S, S'-bis- [2- (N-cyano-N'-methyl) -guanidinoethyl] -disulfide, which crystallizes together with the desired product in organic solvents, is due to the crystallization in water or in aqueous medium carried out reaction and before drying carried out thorough washing of the methylamine with water can be removed. Chromatography was able to detect {the by-product S, S'-bis- [2- (N-cyano-N'-methyl) -guanidinoethyl] -disulfide has on silica gel 60F 254 with a mobile phase of ethyl acetate, acetone and water in a volume ratio of 5 : 4: 1 UV densitometrically at 225 nm measured an R [deep] f value of 0.45} that the proportion of the by-product S, S'-bis- [2- (N-cyano-N'-methyl) -guanidinoäthyl] disulfide when heated to boiling in methylamine solution or when

Drying in the presence of methylamine increases considerably.

The last-mentioned process carried out with aqueous methylamine for the preparation of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidines [cimetidines ] is therefore advantageous both in terms of the course of the reaction and in terms of the purity of the end product.

The invention is therefore based on the object of bringing these advantages to bear even more so that a new derivative of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazole -4 "-yl) -methyl] -thio} -äthyl> -guanidines [Cimetidines] and a process for its preparation, by which an even better separation of the 1-cyano-2-methyl-3- <2 '- {[ (5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidines [cimetidines] is obtained from the aqueous reaction mixture, which improves the production of the crystal modification A of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidines [Cimetidines] enables, as well as a better process for the production of the 1-cyano-2-methyl-3 - <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidines A [Cimetidines A] and also the new derivative of 1-cyano-2-methyl-3 Medicines containing <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidines [cimetidines] g be created.

The above has surprisingly been achieved by the invention.

It has now been found, surprisingly, that if an aqueous warm, possibly also methylamine-containing, homogeneous solution of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) - methyl] -thio} -ethyl> -guanidine [cimetidine] is poured onto ice, from this does not mainly deposit the amorphous 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine B [cimetidine B], but the new monohydrate of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidines [cimetidines], the cimetidine monohydrate, from which the 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine A [cimetidine A] surprisingly easily by recrystallization can be produced. The 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine monohydrate [cimetidine monohydrate] goes slowly into 1 -Cyan-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine A [Cimetidine A] via. This spontaneous process can be accelerated by increasing the temperature.

The invention therefore relates to the new 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine monohydrate [cimetidine monohydrate] of the formula

The 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine monohydrate [cimetidine monohydrate] is a valuable intermediate for the production of the invention 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidines having valuable pharmacological properties

[Cimetidines] through a peculiar process which offers a technically advanced way of producing the latter end product.

The invention also relates to a process for the preparation of the compound according to the invention, which is characterized in that a warm aqueous, optionally also methylamine-containing, homogeneous solution of 1-cyano-2-methyl-3- <2 '- {[(5 " -methylimidazol-4 "-yl) -methyl] -thio} -ethyl> -guanidine [cimetidine] poured onto ice and the precipitated 1-cyano-2-methyl-3- <2 '- {[(5" -methylimidazole- 4 "-yl) -methyl] -thio} -ethyl> -guanidine monohydrate [cimetidine monohydrate] is separated.

Advantageously, the ice is in a weight about the amount of the poured on it solution of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} - ethyl> -guanidine [cimetidine] corresponding amount is used.

The preferred warm, aqueous, homogeneous solution of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine [cimetidine] is used at a temperature of 60 to 80 ° C. The heating is expediently carried out until a clear solution is obtained.

If the solution containing 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine [cimetidine] were cooled relatively slowly, then the crystal modification B of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidines [cimetidines] would be deposited. If, on the other hand, the reaction mixture is cooled to about 20 ° C. or below without the deposition beginning, as is done in the process according to the invention, then it precipitates the solution 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine monohydrate [cimetidine monohydrate] from. An effective way of separating 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine monohydrates [cimetidine monohydrates] is that the boiling aqueous solution, optionally also containing methylamine, of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidines [Cimetidines] is poured onto ice. This pouring on is expediently carried out as quickly as possible. The 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine monohydrate [cimetidine monohydrate] is easy to recognize because it has a well-settling precipitate forms, the washing of which on the filter does not cause any difficulties.

In the process according to the invention, a warm, aqueous homogeneous solution of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine [ Cimetidine] directly one which is obtained by reacting N-cyano-N '- <2 - {[(5'-methylimidazol-4'-yl) -methyl] -thio} -ethyl> -S- <methyl> -isothiourea or of the monohydrate or hydrohalides of the same with methylamine, preferably in a 1 to 4 molar excess, in an aqueous medium, preferably with a reaction time of 2 to 6 hours, at temperatures from 30 ° C. to the boiling point of the solution, preferably up to 90 ° C, in particular, at least during the major part of the reaction time from the beginning to the end, at temperatures of 40 to 60 ° C, very particularly 50 to 55 ° C, and very particularly preferably at temperatures of 70 in the end phase of the reaction to 90 ° C, can be used.

If necessary, the precipitate of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine monohydrate [cimetidine monohydrates] can be removed

Water, expediently by dissolving in this and pouring the boiling solution onto ice, can be recrystallized.

The invention also relates to a process for the preparation of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine A [ Cimetidine A], which is characterized in that the compound according to the invention is prepared from an, optionally aqueous, solvent which is the water of hydration of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazole-4" - yl) -methyl] -thio} -ethyl> -guanidine monohydrates [cimetidine monohydrates] can be removed from this and taken up in itself, is recrystallized.

This is a surprising, peculiar process because it is based on overcoming a prejudice in the prior art (see, for example, German Offenlegungsschrift No. 2,742,531), according to which working in an anhydrous medium is mandatory. In contrast, it was surprisingly found according to the invention that no anhydrous medium is required for recrystallization, since water-containing solvents can also be used.

Advantageous solvents, optionally hydrous alcohols, such as alkanols with 1 to 5 carbon atom (s), especially isopropanol or ethanol, which can be, for example, 96% aqueous ethanol, nitroalkanes with 1 to 3 carbon atom (s), especially Nitromethane or carboxylic acid nitriles with 2 or 3 carbon atoms, especially acetonitrile, are used.

The precipitate of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine monohydrate [cimetidine monohydrate] has such a high dry matter content that he was immediate without drying can be recrystallized to 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine A [cimetidine A]. The recrystallization of the 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} - separated from the solution and containing at most 30% by weight of water ethyl> -guanidine monohydrates [cimetidine monohydrates] to 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine A [cimetidine A ] is preferably carried out from an alkanol, in particular from isopropanol.

The ultra-red spectrum of the 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine monohydrates [cimetidine monohydrates] according to the invention is shown in the accompanying figure 1 and its roentgenogram are shown in the accompanying FIG.

To record the ultrared spectrum, 1 mg sample was homogenized with 300 mg potassium bromide and a lozenge was prepared from the mixture, from which the spectrum was recorded with a spectrophotometer. The X-ray diffraction study was carried out using an HZG 4 / c X-ray diffractometer from Zeiss. The recordings were made with a copper tube (40 kV, 20 mA, Ni filter) at a goniometer speed of 1 ° / minute and a paper speed of 1 cm / minute. The characteristic bands of the ultra-red spectrum and the lattice plane values d calculated from the radiographs are given in Example 1 below.

The results of the known crystal modifications B and C of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl > -guanidines [Cimetidines] X-ray diffraction examinations carried out differ from case to case due to the amorphous structure of the products. That In contrast, 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine monohydrate [cimetidine monohydrate] can always be produced in stable crystal form , its X-ray diffraction spectrum is always the same. The practical significance of the 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine monohydrates [cimetidine monohydrates] according to the invention is that it forms a heavy, sandy, well-settling precipitate, which can be filtered quickly and washed out well and, after suction or centrifugation, contains only 20 to 35% by weight of moisture.

In contrast, the crystal modification B of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidines [cimetidines] forms a very voluminous one , a large part of the solution in itself enclosing precipitate, which contains only 20 to 33 wt .-% dry matter when moist. Washing and drying such precipitates is not an easy task.

Furthermore, pharmaceuticals according to the invention which contain the compound according to the invention 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine monohydrate [cimetidine monohydrate] as an active ingredient, optionally together with 1 or more conventional pharmaceutical formulation (s), provided.

As already mentioned, the 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine monohydrate [cimetidine monohydrate] according to the invention also has itself valuable pharmacological effects, especially the histamine H-2 receptor inhibiting effect.

The invention is illustrated by the following examples explained in more detail.

example 1

1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine monohydrate [cimetidine monohydrate]

A hot solution of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine [cimetidine] was prepared as indicated below ] Poured onto 70 g of ice immediately after preparation. A clear solution with a temperature of 0 to 10 ° C. was obtained. Later the solution became cloudy and granular, well-settling crystals separated out. The solution was placed in a refrigerator for 2 hours and then filtered. The precipitate was washed twice with 10 cm [high] 3 distilled water each time. The wet precipitate weighed 14.8 g. It was dried at 40 ° C. Thus 12.27 g (90.82% of theory) of dry 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl > -guanidine monohydrate [cimetidine monohydrate] with a melting point of 73 to 75 ° C.

Characteristic bands

of the infrared spectrum: 3 502 cm [high] -1, 3 388 cm [high] -1,

3 302 cm [high] -1, 3 042 cm [high] -1,

2 940 cm [high] -1, 2 153 cm [high] -1,

1 594 cm [high] -1, 1 573 cm [high] -1,

1 369 cm [high] -1, 1 258 cm [high] -1,

1,061 cm [high] -1, 1,000 cm [high] -1,

960 cm [high] -1, 723 cm [high] -1, 639 cm [high] -1

and 478 cm [high] -1.

It is also characteristic that at 1,200 cm [high] -1 there is no peak and even at 1,180 cm [high] -1, where the crystal modifications crystallizable from water have the most intense band, only a very weak absorption could be observed.

X-ray distances

diffraction grating planes: 5.851 Angstroms, 4.287 Angstroms, 4.168 Angstroms,

3.743 angstroms, 3.689 angstroms, 3.630 angstroms,

3.424 angstroms, 3.317 angstroms, 3.328 angstroms,

3.195 angstroms, 3.150 angstroms, 2.803 angstroms

and 2.724 angstroms.

10 g of the substance 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine monohydrate [cimetidine monohydrate] obtained above were in 50 cm [high] 3 dissolved water. The boiling solution was poured onto 75 g of ice with stirring. 9.85 g of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine monohydrate [cimetidine monohydrate] separated out , 5% of theory, based on the 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine monohydrate [cimetidine monohydrate ]) with a melting point of 73 ° C and a Karl Fischer water content of 6.5% by weight (theoretical value: 6.67% by weight).

Analysis:

calculated: N = 31.09%;

found: N = 31.30%.

The hot solution of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine [cimetidine] used is described as follows been received.

14.35 g (0.05 mol) of N-cyano-N '- <2 - {[(5'-methylimidazol-4'-yl) -methyl] -thio} -ethyl> -S- <methyl> were obtained -isothiourea monohydrate suspended in 50 cm [high] 3 distilled water. The suspension was stirred or shaken, heated and 18.5 cm [high] 3 of an aqueous methylamine solution with a concentration of 411 g / l (corresponding to 0.245 mol, i.e. 4.9 times the equimolar amount) were added. The reaction mixture was kept on a water bath at a temperature of 50 to 55 ° C. for 2.5 hours, the gas formed being collected and directed to exhaust gas destruction. The mixture became very thin at the beginning and later, without a completely clear solution having formed, 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl began ] -thio} -ethyl> -guanidine to excrete. The mixture became thick; it sometimes happened that the stirrer stopped. After the 2.5 hours had elapsed, the mixture was quickly heated to 80 ° C. and stirred or shaken at this temperature for 1/2 hour. Everything had to dissolve.

The N-cyano-N '- <2 - {[(5'-methylimidazol-4'-yl) -methyl] -thio} -ethyl> -S- <methyl> -isothiourea monohydrate used above has been prepared as described below.

A mixture of 14.8 g (0.1 mol) of 5- (methyl) -4- (hydroxymethyl) imidazole hydrochloride and 11.3 g (0.1 mol) of cysteamine hydrochloride was melted and the melt was at 160 for 15 minutes ° C stirred or shaken. After cooling, the melt was dissolved in 75 cm [high] 3 of water. The solution was successively mixed with 10.6 g (0.1 mol) sodium carbonate, 50 cm [high] 3

Ethanol and 14.6 g (0.1 mol) of dimethyl dithiocarbonate (N-cyano) imide [N-cyanimido-dimethyl carbonate] were added. The reaction mixture was heated to boiling for 1 hour with constant stirring or shaking and, after cooling, stirred or shaken at room temperature for a further 5 to 7 hours. Then the precipitated product was filtered off, washed with water and dried at room temperature. Thus, 23 g (80% of theory) N-cyano-N '- <2 - {[(5'-methylimidazol-4'-yl) methyl] thio} ethyl> -S- <methyl> isothiourea monohydrate obtained with a melting point of 104 to 106 ° C.

Example 2

Preparation of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine A (cimetidine A)

a) There were 23.5 g of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> prepared as described in Example 1 -guanidine monohydrate [cimetidine monohydrate] dissolved in 100 cm [high] 3 isopropanol. The solution was clarified with 0.5 g of charcoal, then filtered and kept together with the precipitate at -5 ° C. for 10 hours. After filtering, 20.96 g (95.5% of theory, based on the 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] used -thio} -ethyl> -guanidine monohydrate [cimetidine monohydrate] 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine A [Cimetidine A] was obtained. b) There were 14.8 g of product (1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} - prepared according to Example 1. Ethyl> -guanidine monohydrate content [cimetidine monohydrate content] = 12.27 g) dissolved in 45 cm [high] 3 isopropanol. The solution was clarified with activated charcoal and then filtered and the 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine obtained A [cimetidine A] was dried. Thus 10.52 g (91.8% of theory, based on the 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -äthyl> -guanidine monohydrate content [cimetidine monohydrate content] of the moist product used) 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> - guanidine A [cimetidine A] was obtained.

Claims (6)

1.) 1-Cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine monohydrate [cimetidine monohydrate] of the formula 2.) Process for the preparation of the compound according to claim 1, characterized in that a warm aqueous, optionally also containing methylamine, homogeneous solution of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazole -4 "-yl) -methyl] -thio} -ethyl> -guanidine [cimetidine] is poured onto ice and the precipitated 1-cyano-2-methyl-3- <2 '- {[(5" -methylimidazole-4 " -yl) -methyl] -thio} -ethyl> -guanidine monohydrate [cimetidine monohydrate] separates. 3.) The method according to claim 2, characterized in that the ice in a weight about the amount of the poured on it solution of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazole-4 "-yl) -methyl] -thio} -ethyl> -guanidine [cimetidine] corresponding amount is used. 4.) Process for the preparation of 1-cyano-2-methyl-3- <2 '- {[(5 "-methylimidazol-4" -yl) -methyl] -thio} -ethyl> -guanidine A [Cimetidine A] , through this characterized in that the compound according to Claim 1 is recrystallized from an optionally aqueous solvent. 5.) The method according to claim 4, characterized in that the solvent used, optionally hydrous, alkanols with 1 to 5 carbon atom (s), nitroalkanes with 1 to 3 carbon atom (s) or carboxonitriles with 2 or 3 carbon atoms. 6.) Medicaments, characterized in that they contain the compound according to claim 1 as active ingredient, optionally together with 1 or more conventional pharmaceutical formulation agent (s).